This invention is directed to treatment of HER-2/neu overexpressing cancers.
The HER-2/neu (erbB-2) gene product is a 185-kDA transmembrane receptor tyrosine kinase that belongs to the family of receptors for epidermal growth factor. It is described in some detail in Reese, D. M., et al., Stem Cells, 15, 1-8 (1997) which is incorporated herein by reference.
Recently, enormous attention has been given to the importance of HER-2/neu in breast cancer. HER-2/neu is overexpressed in 20-30% of human breast cancers and the increased expression has been associated with poor prognosis. The discovery of this has led to the development of HERCEPTIN(copyright), an antibody to HER-2/neu, which in tests has been found to lengthen remission time in metastatic breast cancer. HER-2/neu is a cell-surface receptor that transmits growth signals to the cell nucleus. HERCEPTIN(copyright) appears to block these signals thereby apparently inhibiting proliferation of cells mediated by HER-2/neu in HER-2/neu positive breast cancer.
Overexpression of HER-2/neu has also been found in a portion of ovarian cancers, gastric cancers, endometrial cancers, salivary cancers, pancreatic cancers, prostate cancers, colorectal cancers, and non-small-cell lung cancers. The other cancers associated with overexpression of HER-2-neu are potentially treatable with HERCEPTIN(copyright).
The invention herein is directed to treating cancers associated with overexpression of HER-2/neu with agent different from HERCEPTIN(copyright) or as a supplement to HERCEPTIN(copyright) to block the pathological results of HER-2/neu overexpression and thereby inhibit the development of cancers associated with overexpression of HER-2/neu.
It is shown herein that HER-2/neu expression causes increase of c-Jun and it is posited that the c-Jun induces cyclooxygenase-2 (COX-2) gene expression via the cyclic AMP response element and that this results in overexpression of COX-2 which mediates tumor formation. It is concluded from this that cancers associated with overexpression of HER-2/neu expression are beneficially treated with selective inhibitors of cyclooxygenase-2.
In a broad embodiment, the invention is directed at a method of treating cancer associated with overexpression of HER-2/neu in a patient affected with this condition, comprising administering to said patient a therapeutically effective amount of a selective inhibitor of cyclooxygenase-2. The cyclooxygenase-2 inhibitor can be administered as the only therapy or in a combination regimen with a therapeutically effective amount of HERCEPTIN(copyright), a HER-2/neu antibody available from Genentech, and/or conventional therapy for the kind of cancer being treated.
In a narrower embodiment, the invention is directed at a method of treating breast cancer associated with overexpression of HER-2/neu in a patient affected with this condition comprising administering to said patient a therapeutically effective amount of a selective inhibitor of cyclooxygenase-2. The cyclooxygenase-2 inhibitor can be administered for or as part of adjuvant therapy for HER-2/neu positive breast cancer or for treatment of or as part treatment of HER-2/neu positive breast cancer that has metastasized. The cyclooxygenase-2 inhibitor is preferably administered in a combination regimen with HERCEPTIN(copyright) and preferably also is administered in combination regimen with standard chemotherapy or endocrine therapy or radiation treatment.
The term xe2x80x9ccancer associated with overexpression of HER-2/neuxe2x80x9d is used herein to mean that cancerous tissue contains more HER-2/neu than non-cancerous tissue from the same portion of the body.
The term xe2x80x9cHER-2/neu positive breast cancerxe2x80x9d is used herein to mean breast cancer associated with overexpression of HER-2/neu.
The cancers associated with overexpression of HER-2/neu include all those cancers where overexpression of HER-2/neu is found in cancerous tissue and comprise breast cancers, ovarian cancers, gastric cancers, endometrial cancers, salivary cancers, pancreatic cancers, prostate cancers, colorectal cancers and non-small-cell lung cancers, where overexpression of HER-2/neu is found in the cancerous tissue.
Assays for HER-2/neu overexpression have been developed or are under development. These include the Vysis PathVysion HER2 DNA Probe Kit developed by Vysis Inc., Downer""s Grove, Ill., which is based on fluorescent in situ hybridization and a diagnostic kit being developed by DAKO A/S of Glostrup, Denmark which is directed to detecting antibodies to the HER-2/neu protein based on immunohistochemistry.
We turn now to the selective inhibitors of cyclooxygenase-2. The selective inhibitors of cyclooxygenase-2 are synthetic compounds.
The selective inhibitors of cyclooxygenase-2 are preferably those where the ratio of the IC50 concentration for cyclooxygenase-1 to the IC50 concentration for cyclooxygenase-2 is 5 or more, very preferably 100 or more.
Selective inhibitors of cyclooxygenase-2 include the following compounds:
(1) 4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(2) 4-[5-(4-Bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(3) 4-[5-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(4) 4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(5) 4-[5-(2-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(6) 4-[5-(4-Trifluoromethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(7) 4-[5-(4-Fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(8) 4-[5-Phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(9) 4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(10) 4-[5-(4-Trifluoromethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(12) 4-[5-(2-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(12) 4-[5-(4-Chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(13) 4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-carboxylate
(14) 4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-carboxamide
(15) 4-[5-(4-[Methylthio]phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(16) 4-[5-(4-[Methylsulfonyl]phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(17) 4-[5-(2,4-[Difluoro]phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(18) 4-[5-(2,6-[Difluoro]phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(19) 4-[5-(4-Cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(20) 4-[5-(4-Chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazol-1-yl]benzenesulfonamide
(21) 4-[5-(4-Chlorophenyl)-3-(chloro-difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(22) 4-[5-(4-Chlorophenyl)-3-(pentafluoroethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(23) 4-[5-(4-Biphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(24) 4-[5-(4-Pyrazinyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(25) 4-[5-(5-Chloro-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(26) 4-[5-(4-Morpholino)phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(27) 4-[5-(1-Cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(28) 4-[5-(5-Bromo-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(29) 4-[5-(4-Thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(30) 4-[5-(4-[Trifluoromethyl]phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(31) 4-[5-(3,4-Dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(32) 4-[5-(2,4-Dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(33) 4-[5-Phenyl-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide
(34) 4-[5-(4-Fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide
(35) 4-[4-(Aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole]-3-propanoic acid
(36) 4,5-Dihydro-4-[3-trifluoromethyl]-1H-benz[g]indazol-1-yl]benzenesulfonamide
(37) 4-[5-(4-Chlorophenyl)-4-chloro-1H-pyrazol-1-yl]benzenesulfonamide
(38) 4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-4-chloro-1H-pyrazol-1-yl]benzenesulfonamide
(39) 4-[1-(4-Fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide
(40) 1-(2,4,6-Trichlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetic acid
(41) 1-(2,6-dichlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetic acid
(42) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-hydroxy-2-propyl)thiophene
(43) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene
(44) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-propyl)thiophene
(45) 3-(4-(Aminosulfonyl)phenyl)-2-cyclohexylthiophene
(46) 5-(4-Carboxyphenyl)-4-(4-(methylsulfonyl)phenyl)thiophene-2-carboxylic acid
(47) 4-(4-Fluorophenyl)-2-methyl-5-(4-(methylsulfonyl) phenyl)thiazole
(48) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one
(49) 4-(4-(Methylsulfonyl)phenyl-5-(4-fluorophenyl)-isothiazole
(50) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl-2-(5H)-furanone
(51) 3-(4-Fluorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone
(52) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)furan
(53) 5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)furanone
(54) 2-((4-Aminosulfonyl)phenyl)-3-(4-fluorophenyl)thiophene
(55) 3-(2,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(56) 3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(57) 3-(2,6-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(58) 3-(2,5-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(59) 3-(3,5-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(60) 3-(4-Bromophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(61) 3-(4-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(62) 3-(4-Methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(63) 3-(Phenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(64) 3-(2-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(65) 3-(2-Bromo-4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(66) 3-(2-Bromo-4-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(67) 3-(4-Chloro-2-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(68) 3-(3-Bromo-4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(69) 3-(3-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(70) 3-(2-Chloro-4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(71) 3-(2,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(72) 3-(3,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(73) 3-(2,6-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(74) 3-(3-Chloro-4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(75) 3-(4-Trifluoromethylphenyl)-4-(4-(methylsulfonyl)phenyl)2-(5H)-furanone
(76) 3-(3-Fluoro-4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(77) 3-(3-Chloro-4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)furanone
(78) 3-(3-Bromo-4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(79) 3-(2-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(80) 3-(4-Methylthiophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(81) 3-(3-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(82) 3-(2-Chloro-6-fluorophenyl)4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(83) 3-(3-Bromo-4-methylphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(84) 3-(4-Bromo-2-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(85) 3-(3,4-Dibromophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(86) 3-(4-Chloro-3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(87) 3-(4-Bromo-3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(88) 3-(4-Bromo-2-chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(89) 3-(2-Naphthyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(90) 3-(7-Quinolinyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(91) 3-(3,4-Dichlorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone
(92) 3-(3,4-Dichlorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone
(93) 3-(3,4-Dichlorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone
(94) 3-(3-Bromo-4-methoxyphenyl)4-(4-(aminosulfonyl)phenyl)-2-(2H)furanone
(95) 3-(4-(Methylsulfonyl)phenyl)-2-phenylbenzo[b]furan
(96) 3-(4-Methylsulfonyl)phenyl)-2-phenylbenzo[b]thiophene
(97) 3-(4-Methylsulfonyl)phenyl)-2-phenylinden-1-one
(98) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)indole
(99) 3-(4-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)indole
(100) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-4H-thieno[2,3-c]-furan-6-one
(101) 2-(3,4-Difluorophenyl)-3-(4-(methylsulfonyl)phenyl)-4H-thieno[2,3-c]-furan-6-one
(102) 2-(4-Fluorophenyl)-3-(4-(aminosulfonyl)phenyl)-4H-thieno[2,3-c]-furan-6-one
(103) 2-(3,4-Difluorophenyl)-3-(4-(aminosulfonyl)phenyl)-4H-thieno[2,3-c]-furan-6-one
(104) 3-(4-(Methylsulfonyl)phenyl)-2-phenyl)-4,7-dihydrothieno[2,3-c]pyran-5-one
(105) 2-(4-(Methylsulfonyl)phenyl)-3-phenyl)-4H-thieno[2,3-c]furan-6-one
(106) 5-(4-(Methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]thiazole
(107) 2-Methyl-5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]thiazole
(108) 3-Methyl-5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]thiazole
(109) 2-Bromo-5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]thiazole
(110) 3-Trifluoromethyl-5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]thiazole
(111) 2,3-Dimethyl-5-(4-(methylsulfonyl)phenyl)-6-phenyl-imidazo[2,1-b]thiazole
(112) 5-(4-(Methylsulfonyl)phenyl)-6-(4-fluorophenyl)imidazo[2,1-b]thiazole
(113) 5-Phenyl)-6-(4-(methylsulfonyl)phenyl)-imidazo[2,1-b]thiazole
(114) 2-Chloro-5-(4-(methylsulfonyl)phenyl)-6-(4-chlorophenyl)imidazo[2,1-b]thiazole
(115) 2,2-Dichloro-5-(4-(methylsulfonyl)phenyl)-6-(4-chlorophenyl)imidazo[2,1-b]thiazole
(116) 5-(4-(Methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]-1,3,4-thiadiazole
(117) 5-Phenyl-6-(4-(methylsulfonyl)phenyl)imidazo[2,1-b]-1,3,4-thiadiazole
(118) 2-Methyl-5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]-1,3,4-thiadiazole
(119) 2-Methyl-5-phenyl-6-(4-methylsulfonyl)phenyl)imidazo[2,1-b]-1,3,4-thiadiazole
(120) 5-(4-(Methylsulfonyl)phenyl)-6-(4-fluorophenyl)-imidazo[2,1-b]-1,3,4-thiadiazole
(121) 5-(4-(Methylsulfonyl)phenyl)-6-phenyl-1H-imidazo[2,1-b]-s-triazole
(122) 5-Phenyl-6-(4-(methylsulfonyl)phenyl)thiazolo[3,2-b]-1,3,4-triazole
(123) 2,3-Dihydro-5-(4-(methylsulfonyl)phenyl)6-phenylimidazo[2,1-b]thiazole
(124) 2-[(4-Methylthio)phenyl]-1-biphenyl
(125) 1-Cyclohexene-2-(4xe2x80x2-methylsulfonylphenyl)benzene
(126) 3-(4xe2x80x2-Methylsulfonylphenyl)-4-phenylphenol
(127) 1-[2-(4-Methylsulfonylphenyl)phenyl]piperidine
(128) 1-[2-(4xe2x80x2-Methylsulfonylphenyl)phenyl]pyrrole
(129) 1-Phenoxy-2-(4xe2x80x2-methylsulfonylphenyl)benzene
(130) 5-(4-fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine
(131) 2-Ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine
(132) 5-(4-Fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-propynyloxy)-6-(trifluoromethyl)pyridine
(133) 2-Bromo-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine
(134) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]propanoic acid
(135) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]butanoic acid, sodium salt
(136) 2-Benzyl-3-[1-(p-bromobenzyl)-5-methoxy-2-methylindol-3-yl-propanoic acid
(137) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2,2-dimethylpropanoic acid
(138) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-4,4,4-trifluorobutanoic acid, sodium salt
(139) trans-2-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-cyclopropanecarboxylic acid, sodium salt
(140) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-hydroxy-2-methylpropanoic acid, sodium salt
(141) [1-(1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-cyclopropylacetic acid, sodium salt
(142) trans-(+)-2-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]cyclopropanecarboxylic acid, sodium salt
(143) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2-methylpropanoic acid and sodium salt
(144) 3-[1-(p-Chlorobenzyl)-5-methoxy-2-methylindol-3-yl]-4,4,4-trifluorobutanoic acid and sodium salt
(145) syn-3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2-methylbutanoic acid
(146) anti-3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2-methylbutanoic acid and sodium salt
(147) 3-[5-(Bromo-1-(p-bromobenzyl)-2-methylindol-3-yl]butanoic acid and sodium salt
(148) (xe2x88x92)-3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-butanoic acid and sodium salt
(149) (+)3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-butanoic acid and sodium salt
(150) trans-(xe2x88x92)-2-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]cyclopropanecarboxylic acid and sodium salt
(151) 3-[1-(p-Bromobenzyl)-2,5-dimethylindol-3-yl]propanoic acid
(152) 3-[5-(Bromo-1-(p-bromobenzyl)-2-methylindol-3-yl]propanoic acid
(153) 3-[1-(p-Bromobenzyl)-5-chloro-2-methylindol-3-yl)propanoic acid
(154) 3-[1-(p-Chlorobenzyl)-5-methoxy-2-methylindol-3-yl)-2-methylpropanoic acid
(155) Methyl 3-[1-(p-bromobenzyl)-5-methoxy-2-methylindol-3-yl)propanoate
(156) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl)-3-methylbutanoic acid
(157) 5-Methanesulfonamido-6-(2,4-difluorophenylthio)-1-indanone
(158) 5-Methanesulfonamido-6-(2,4-dichlorophenoxy)-1-indanone
(159) 2-(4-Chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole
(160) 2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole
(161) 1-(4-Fluorophenyl)-4-hydroxy-2-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole
(162) 1-(4-Fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole
(163) 2-(4-Chlorophenyl)-1-[4-methylsulfonyl)phenyl]-4-methyl-1H-imidazole
(164) 2-(4-Chlorophenyl)-1-[4-methylsulfonyl)phenyl]-4-phenyl-1H-imidazole
(165) 2-(4-Chlorophenyl)-4-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(166) 4-(4-Bromophenyl)-2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(167) 2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(2-naphthyl)-1H-imidazole
(168) 2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-[4-(trifluoromethoxy)phenyl]-1H-imidazole
(169) 2,4-Bis(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(170) 2-(4-Chlorophenyl)-4-(3-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(171) 2-(4-Chlorophenyl)-4-(4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(172) 2-(4-Chlorophenyl)-4-(3-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(173) 2-(4-Chlorophenyl)-4-[(4-chlorophenoxy)methyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(174) 2-(3-Chloro-4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole
(175) 5-[1-[4-(Methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-imidazole-2-yl]-1,3-benzodioxole
(176) 2-(3-Fluoro-4-methoxyphenyl)-1-[4-(methylsulfonyl)-phenyl-4-(trifluoromethyl)-1H-imidazole
(177) 2-(4-Chlorophenyl)-4-[(phenylthio)methyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(178) 2-(4-Chlorophenyl)-4-[(N-methyl-N-phenylamino)methyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(179) 2-(4-Chlorophenyl)-4-[2-quinolyl)methoxymethyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(180) 2-(4-Chlorophenyl)-4-methoxymethyl-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(181) 2-(4-Fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole
(182) 1-[4-(Methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-1H-imidazole
(183) 2-(3-Chloro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole
(184) 2-(4-Methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole
(185) 1-[4-(Methylsulfonyl)phenyl]-2-(4-trifluoromethyl-phenyl)-4-trifluoromethyl-1H-imidazole
(186) 4-[2-(4-Chlorophenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
(187) 4-[2-(3-Chloro-4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
(188) 3-[1-(4-Methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
(189) 2-[1-(4-Methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
(190) 4-[1-[4-(Methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
(191) 2-Methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
(192) 2-Methyl-6-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
(193) 5-Methyl-2-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
(194) 4-Methyl-2-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
(195) 2-Methoxy-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
(196) 4-[2-(6-Methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
(197) 4-[2-(6-Methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
(198) 3-Methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine
(199) 4-[2-(4-Methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
(200) 2-[1-[4-(Methylsulfonyl)phenyl]-4-(trifluoromethyl) 1H-imidazol-2-yl]thiophene
(201) 3-[1-[4-(Methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]thiophene
(202) 4-[2-(5-Methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
(203) 2-Methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]thiophene
(204) 4-[2-(2-Methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
(205) 4-[2-Pyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
The synthesis of compounds 1-39 is disclosed in Talley et al. U.S. Pat. No. 5,466,823. The synthesis of compounds 40 and 41 is disclosed in Black et al. U.S. Pat. No. 5,436,265. The synthesis of compounds 42-94 is disclosed in Ducharme et al. U.S. Pat. No. 5,474,995. The synthesis of compounds 95-105 is disclosed in Prasit et al. U.S. Pat. No. 5,521,213. The synthesis of compounds 106-123 is disclosed in Gauthier et al. U.S. Pat. No. 5,552,422. The synthesis of compounds 124-129 is disclosed in Batt U.S. Pat. No. 5,593,994. The synthesis of compounds 130-133 is disclosed in Lee U.S. Pat. No. 5,596,008. The synthesis of compounds 134-156 is disclosed in Lau et al. U.S. Pat. No. 5,604,253. The synthesis of compounds 157 and 158 is disclosed in Guay et al. U.S. Pat. No. 5,604,260. The synthesis of compounds 159-205 is disclosed in Khanna et al. U.S. Pat. No. 5,616,601.
Other selective inhibitors of cyclooxygenase-2 and their synthesis are taught in Examples 2-108, 110-129, 131-150, 152, 301-312, and 401-413 of Batt et al. U.S. Pat. No. 5,593,994, the disclosure of which is incorporated herein by reference. Still other selective inhibitors of cyclooxygenase-2 and their synthesis are taught in Examples 1-11, 13-16, and 18-25 of Guay et al. U.S. Pat. No. 5,604,260, the disclosure of which is incorporated herein by reference. Still other selective inhibitors of cyclooxygenase-2 and their synthesis are taught in Examples 1-13 including Examples 1a-1p and 4a-4h of Talley et al. U.S. Pat. No. 5,633,272, the disclosure of which is incorporated herein by reference. Still other selective inhibitors of cyclooxygenase-2 are taught in Examples 1-131 of Lau et al. U.S. Pat. No. 5,639,780, the disclosure of which is incorporated herein by reference. Still other selective inhibitors of cyclooxygenase-2 are taught in Examples 1-6 of Talley et al. U.S. Pat. No. 5,643,933, the disclosure of which is incorporated herein by reference. Still other selective inhibitors of cyclooxygenase-2 are taught in Examples 1-4 of Lau et al. U.S. Pat. No. 5,510,368, the disclosure of which is incorporated herein by reference.
Preferred inhibitors of cyclooxygenase-2 for use herein are 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide which is compound (1) set forth above and 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide which is compound (4) set forth above; it is believed the latter compound is celicoxib (Trade name Celebrex(copyright)). Another preferred selective inhibitor of cyclooxygenase-2 is Vioxx(copyright) which is MK-0966; it is compound (63) set forth above.
Other preferred selective inhibitors of cyclooxygenase-2 are inhibitors of cyclooxygenase-2 which directly and selectively inhibit the enzyme cyclooxygenase-2 and also inhibit the synthesis of cyclooxygenase-2 protein and also have antioxidant properties. These selective inhibitors of cyclooxygenase-2 preferably contain phenyl group with two or more substituents selected from the group consisting of hydroxy and C1-4-alkoxy (e.g., methoxy) on the phenyl. Such compounds are embraced by generic description in various patents but no species of selective cyclooxygenase-2 inhibitor containing phenyl group with two or more hydroxy or alkoxy substituents is disclosed in any of said patents. The patents referred to are: Talley et al. U.S. Pat. No. 5,643,933; Talley et al. U.S. Pat. No. 5,633,272; Khanna et al. U.S. Pat. No. 5,616,601; Lee U.S. Pat. No. 5,596,008; Batt et al. U.S. Pat. No. 5,593,994; and Adams et al. U.S. Pat. No. 5,593,992. Specific compounds for this kind of selective inhibitor of cyclooxygenase-2 include, for example, 4-[5-methyl-3-[[(2,3-hydroxy)phenoxy]methyl]-1H-pyrazol-1-yl]benzenesulfonamide and 4-methyl-5-(4-methylsulfonyl)phenyl-2-[(2,3-hydroxy)phenoxy]methyl]oxazole and the corresponding compounds where methoxy or ethoxy replaces hydroxy. 4-[5-Methyl-3-[[(2,3-hydroxy)phenoxy]methyl]-1H-pyrazol-1-yl]benzenesulfonamide has the structure 
where R1 is methyl and R2 is NH2. 4-(Methyl)-5-(4-methylsulfonyl)phenyl-2-[(2,3-hydroxyphenoxy)methyl]oxazole has the structure

These compounds are embraced by broad disclosure in Talley et al. U.S. Pat. No. 5,643,933 but are not specifically disclosed therein. These compounds can be made analogously to Scheme XXII in U.S. Pat. No. 5,643,933 by reacting 2,3-dihydroxybenzyl bromide, where the hydroxy groups are protected by conventional techniques (for example, as described in E. Haslam, xe2x80x9cProtection of Phenols and Catecholsxe2x80x9d pages 145-182, in Protective Groups in Organic Chemistry, McOmie, J. F. W., editor, Plenum Press, London (1973)), with alcohol corresponding to the product sought, in the presence of base, and deprotecting, and in the case of the methoxy or ethoxy compounds with alkoxy substituents in phenyl moiety, replacing the hydroxy substituents with alkoxy. Alternatively, these compounds can be made by reacting said alcohol with mesyl chloride to yield the unstable mesylate and then reacting with appropriate trihydroxyphenol. These compounds directly inhibit the cyclooxygenase-2 enzyme and also inhibit the synthesis of cyclooxygenase-2.
The dosage of selective inhibitor of cyclooxygenase-2 for the method of the broad embodiment herein is a cyclooxygenase-2 inhibiting amount which is a therapeutically effective amount, i.e., a cancer cell growth inhibiting amount. In general, the dosage ranges from 0.1 to 30 mg/kg. The dosages for any particular agent will vary within said range. For compound (4) referred to above, the dosage preferably ranges from 3 to 15 mg/kg, e.g., preferably is 12 mg/kg. For compound (63) referred to above, the dosage normally ranges from 12.5 to 50 mg daily. The route of administration is preferably systemic, e.g., oral or parenteral, e.g., intravenous.
We turn now to the embodiment directed at a method of treating breast cancer associated with overexpression of HER-2/neu in a patient affected with this condition comprising administering to said patient a therapeutically effective amount of a selective inhibitor of cyclooxygenase-2.
Primary treatment in the case of those determined to have breast cancer is mastectomy or breast conserving surgery (lumpectomy, tylectomy, wide excision, partial mastectomy, or quadrantectomy) plus radiation therapy.
Adjuvant systemic therapy is begun soon after primary therapy to delay recurrence and/or to prolong survival.
Breast cancer may metastasize to almost any organ in the body. Those most commonly involved include the lung, liver, bone, lymph nodes, and skin. Breast cancer also may metastasize to the central nervous system.
As indicated above, the invention herein is applicable to adjuvant therapy for HER-2/neu positive breast cancer and to treating HER-2/neu breast cancer that has metastasized.
The presence of HER-2/neu positive breast cancer is diagnosed by assays for HER-2/neu overexpression, e.g., as described above, carried out on breast cancer tissue.
The selective inhibitors of cyclooxygenase-2 for use in treating HER-2/neu positive breast cancer are those useful for treating cancers associated with the overexpression of HER-2/neu as described above and the dosages and routes of administration for these for treating HER-2/neu positive breast cancer are those described above in connection with treating cancers associated with the overexpression of HER-2/neu, and for adjuvant therapy for breast cancer, a therapeutically effective amount is a breast cancer cell growth inhibiting amount, and for treating breast cancer that has metastasized, a therapeutically effective amount is a metastatic cell growth inhibiting amount. For adjuvant therapy, administration is continued for two to five years. In the case of metastasized breast cancer, treatment is preferably continued until no further response is seen.
As indicated above, the inhibitors of cyclooxygenase-2 may be used as the sole treatment agent in treating HER-2/neu positive breast cancer. However, the inhibitors of cyclooxygenase-2 are preferably utilized in a combination regimen, for example, with HERCEPTIN(copyright). When HERCEPTIN(copyright) is used as part of the therapy, a loading dose of 4 mg/kg IV is given followed by a weekly maintenance dose of 2 mg/kg IV. The inhibitors of cyclooxygenase-2 are also preferably used in combination regimen with standard therapy. One kind of standard adjuvant therapy is adjuvant chemotherapy, e.g., using a combination regimen of cyclophosphamide, methotrexate and 5-fluorouracil, e.g., for four to 24 months. Another kind of adjuvant systemic therapy is adjuvant tamoxifen therapy given for two to five years. Adjuvant chemotherapy is given routinely to all pre-menopausal, node-positive patients. Adjuvant tamoxifen therapy is given routinely to post-menopausal women who are node positive and have estrogen-receptor positive tumors. Standard therapies for patients with metastatic disease include endocrine therapy or chemotherapy or in some cases radiation therapy to palliate symptoms. Chemotherapies used for treating metastatic disease include paclitaxel (Taxol(copyright)) or a combination regimen of cyclophosphamide (Cytoxan(copyright)) and doxorubicin (Adriamycin(copyright)). Treatments herein for metastatic HER-2/neu positive breast cancer include a therapeutically effective amount of a selective inhibitor of cyclooxygenase-2 used in a combination regimen with HERCEPTIN(copyright) plus a conventional dosage of paclitaxel or used in a combination therapy with HERCEPTIN(copyright) plus a conventional dosage of cyclophosphamide and doxorubicin.
As indicated above, this application claims the benefit of U.S. Provisional Application No. 60/117,466. The entire disclosure of U.S. Provisional Application No. 60/117,466 is incorporated herein by reference.